Axon pruning or degeneration occurs widely during development, as part of axonal rearrangements following injury and in adult plasticity, and is a major pathological feature of most neurodegenerative diseases. However, the molecular mechanisms that initiate and execute axon degeneration in these diverse settings remain incompletely understood. Recently, we identified a caspase-dependent pathway that regulates axon degeneration both in vitro and in vivo. These findings have provided a new entry point for determining the molecular components that regulate axon degeneration. This proposal is focused on identifying key components of the biochemical pathway of caspase-dependent axon degeneration that lead to degeneration in the developing and diseased peripheral nervous system. We will use complementary approaches to (i) rapidly screen mice mutant for various pathway components to determine which ones regulate degeneration of developing sensory and motor axons in response to trophic deprivation in vitro, (ii) identify additional components of the degeneration pathway through biochemical analysis and siRNA screening, (iii) elucidate mechanisms of caspase regulation (iv) determine the contribution of the apoptotic pathway to developmental axon pruning in vivo, and (v) test for disease relevance by crossing relevant mutants to a mouse model of sensory axon degeneration. These studies will identify novel mechanisms regulating developmental and pathological axon degeneration, including potential therapeutic targets.